Small molecule modulators of pantothenate kinases

ABSTRACT

The present disclosure relates to chemical compounds that modulate pantothenate kinase (PanK) activity for the treatment of metabolic disorders (such as diabetes mellitus type II), neurologic disorders (such as pantothenate kinase-associated neurodegeneration), pharmaceutical compositions containing such compounds, and their use in treatment. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage Entry under § 371 ofInternational Application No. PCT/US2018/067539, filed Dec. 26, 2018,which claims the benefit of U.S. Provisional Application No. 62/610,835,filed on Dec. 27, 2017, the contents of which is incorporated herein byreference in its entirety.

BACKGROUND

Pantothenate Kinase (PanK, EC 2.7.1.33) catalyzes the biochemicalconversion of pantothenate (vitamin B5) to phosphopantothenate andthereby initiates the biosynthesis of coenzyme A (CoA). In mostorganisms the activities of the PanK enzymes regulate the CoAintracellular concentration (Leonardi et al. (2005) Prog. Lipid Res. 44:125-153; Jackowski and Rock (1981) J. Bacteriol. 148: 926-932; Zano etal. (2015) Mol. Genet. Metab. 116:281-288). CoA is an essential cofactorthat functions as a carboxylic acid substrate carrier in varioussynthetic and oxidative metabolic pathways, such as the tricarboxylicacid cycle, sterol biosynthesis, heme biosynthesis, fatty acid andcomplex lipid synthesis and metabolism, and epigenetic modification ofchromatin. Four closely related active PanK isoforms are identified inmammals: PanK1α, PanK1β, PanK2, and PanK3, which are encoded by threegenes (Zhou et al. (2001) Nat. Genet. 28: 345-349; Zhang et al. (2005)J. Biol. Chem. 280: 32594-32601; Rock et al. (2002) Gene 291: 35-43).The PanKs regulate cellular CoA through feedback inhibition of theenzyme activity by CoA or CoA thioesters and each isoform responds toinhibition with a different sensitivity (Leonardi et al. (2005) Prog.Lipid Res. 44: 125-153). The PanK isoform expression profiles differamong individual cell types, tissues and organs and the relativeabundance of one or more isoforms determines the respective CoA levels(Dansie et al. (2014) Biochem. Soc. Trans. 42:1033-1036).

Mutations in the human PANK2 gene result in a rare and life-threateningneurological disorder known as PanK-associated neurodegeneration (PKAN)(Zhou et al. (2001) Nat. Genet. 28: 345-349; Johnson et al. (2004) Ann.N. Y. Acad. Sci. 1012: 282-298; Kotzbauer et al. (2005) J. Neurosci. 25:689-698). PKAN is an inherited autosomal recessive disorder that leadsto progressive dystonia, dysarthria, parkinsonism, and pigmentaryretinopathy. Classic PKAN develops in the first 10 years of life,starting around age 3; and patients are at risk for early death. ThePANK2 gene is highly expressed in human neuronal tissues and many of themutations associated with PKAN result in truncated or inactivated PanK2protein expression, or severely reduced activity (Zhang et al. (2006) J.Biol. Chem. 281:107-114). The PANK2 mutations are predicted to result insignificantly lower CoA levels, thereby reducing neuronal metabolism andfunction in PKAN patients. Tools are lacking for investigation of therelationship(s) between CoA levels and neurodegeneration. Activation ofthe PanK1 or PanK3 proteins that are also expressed in neuronal tissues(Leonardi et al. (2007) FEBS Lett. 581:4639-4644) could compensate forthe reduction in PanK2 activity because functional redundancy among theisoforms is demonstrated in the Pank1^(−/−) and Pank2^(−/−) mouse models(Leonardi et al. (2010).

Limitation of the CoA supply by genetic deletion of Pank1 in mice bluntsthe increase in hepatic CoA in response to fasting. This, in turn,decreases fatty acid oxidation and glucose production by the liverresulting in fasting hypoglycemia (Leonardi et al. (2010) PloS one 5:e11107). Hypoglycemia and a significant reduction in fatty acid andketone oxidation are the main causes for the early death of thePank1^(−/−) Pank2¹ mice in which both genes are deleted (Garcia et al.(2012) PLoS one 7: e40871). The ob/ob leptin-deficient mouse is a modelof obesity-associated type II diabetes that exhibits abnormally highhepatic CoA (Leonardi et al. (2014) Diabetologia 57: 1466-1475).Consistent with the connection between hepatic CoA levels and glucosehomeostasis, deletion of Pank1 in the ob/ob mouse reduces hepatic CoAand results in normalization of the diabetic hyperglycemia andassociated hyperinsulinemia characteristic of this strain (Leonardi etal. (2014) Diabetologia 57: 1466-1475). A genome-wide association study(Sabatti et al. (2009) Nature Genet. 41: 35-46) indicates a significantcorrelation between PANK1 gene variants and insulin levels in humans,supporting the concept that PanK inhibitors may be useful therapeuticsfor diabetes. Taken together, these data demonstrate the impact ofaltering the intracellular level of CoA on oxidative metabolism andglucose homeostasis.

The associations of PanK with diseases like PKAN and diabetes led us toidentify and develop PanK activators and inhibitors capable ofmodulating CoA levels and to assess the feasibility of such compounds astherapeutics in these diseases. We recently disclosed our initial highthroughput screening effort towards this goal (Sharma et. al. (2015) J.Med. Chem. 58: 1563-1568). Our subsequent re-examination, carefulfilteration of hits and medicinal chemistry efforts identified newchemotypes capable of modulating PanK activity.

Despite the documented association of PanK with diseases like PKAN anddiabetes, the feasibility of PanK antagonists capable of modulating CoAlevels as disease therapeutics is uncertain. Thus, there remains a needfor potent modulators of PanK to investigate the role of CoA in disease.The following disclosure describes a group of such compounds, as well asmethods for making and using them.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tocompositions and methods for use in the prevention and treatment ofdisorders associated with pantothenate kinase activity such as, forexample, PKAN and diabetes.

Disclosed are compounds having a structure represented by a formula:

wherein Q² is a structure selected from:

wherein each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, provided at leastone of R^(3a), R^(3b), and R^(3c) is halogen; and wherein R⁴ is selectedform hydrogen, halogen, —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃, and NO₂, or apharmaceutically acceptable salt thereof.

Also disclosed are compounds having a structure represented by aformula:

wherein A is selected from O, CO, CH₂, CF₂, NH, N(CH₃), and CH(OH);wherein each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, provided at leastone of R^(3a), R^(3b), and R^(3c) is halogen; and wherein R⁴ is selectedform hydrogen, halogen, —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃, and NO₂, or apharmaceutically acceptable salt thereof.

Also disclosed are methods of making a disclosed compound.

Also disclosed are pharmaceutical compositions comprising at least onedisclosed compound.

Also disclosed are methods of modulating pantothenate kinase activity inat least one cell, the method comprising the step of contacting at leastone cell with an effective amount of at least one disclosed compound, ora pharmaceutically acceptable salt thereof.

Also disclosed are methods of treating a disorder associated withpantothenate kinase activity in a subject, the method comprisingadministering to the subject an effective amount of at least onedisclosed compound, or a pharmaceutically acceptable salt thereof.

Also disclosed are the method of modulating Coenzyme A levels in cellswith an effective amount of at least one disclosed compound, or apharmaceutically acceptable salt thereof or in combination withPantothenate and its derivatives.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. DEFINITIONS

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

As used in the specification and in the claims, the term “comprising”can include the aspects “consisting of” and “consisting essentially of.”

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, another aspect includes from the one particular value and/orto the other particular value. Similarly, when values are expressed asapproximations, by use of the antecedent “about,” it will be understoodthat the particular value forms another aspect. It will be furtherunderstood that the endpoints of each of the ranges are significant bothin relation to the other endpoint, and independently of the otherendpoint. It is also understood that there are a number of valuesdisclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

As used herein, the terms “about” and “at or about” mean that the amountor value in question can be the value designated some other valueapproximately or about the same. It is generally understood, as usedherein, that it is the nominal value indicated ±10% variation unlessotherwise indicated or inferred. The term is intended to convey thatsimilar values promote equivalent results or effects recited in theclaims. That is, it is understood that amounts, sizes, formulations,parameters, and other quantities and characteristics are not and neednot be exact, but can be approximate and/or larger or smaller, asdesired, reflecting tolerances, conversion factors, rounding off,measurement error and the like, and other factors known to those ofskill in the art. In general, an amount, size, formulation, parameter orother quantity or characteristic is “about” or “approximate” whether ornot expressly stated to be such. It is understood that where “about” isused before a quantitative value, the parameter also includes thespecific quantitative value itself, unless specifically statedotherwise.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “subject” can be a vertebrate, such as amammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject ofthe herein disclosed methods can be a human, non-human primate, horse,pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The termdoes not denote a particular age or sex. Thus, adult and newbornsubjects, as well as fetuses, whether male or female, are intended to becovered. In one aspect, the subject is a mammal A patient refers to asubject afflicted with a disease or disorder. The term “patient”includes human and veterinary subjects.

As used herein, the term “treatment” refers to the medical management ofa patient with the intent to cure, ameliorate, stabilize, or prevent adisease, pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder. In various aspects, the term covers anytreatment of a subject, including a mammal (e.g., a human), andincludes: (i) preventing the disease from occurring in a subject thatcan be predisposed to the disease but has not yet been diagnosed ashaving it; (ii) inhibiting the disease, i.e., arresting its development;or (iii) relieving the disease, i.e., causing regression of the disease.In one aspect, the subject is a mammal such as a primate, and, in afurther aspect, the subject is a human. The term “subject” also includesdomesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse,rabbit, rat, guinea pig, fruit fly, etc.).

As used herein, the term “prevent” or “preventing” refers to precluding,averting, obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action. It is understood that wherereduce, inhibit or prevent are used herein, unless specificallyindicated otherwise, the use of the other two words is also expresslydisclosed.

As used herein, the term “diagnosed” means having been subjected to aphysical examination by a person of skill, for example, a physician, andfound to have a condition that can be diagnosed or treated by thecompounds, compositions, or methods disclosed herein.

As used herein, the terms “administering” and “administration” refer toany method of providing a pharmaceutical preparation to a subject. Suchmethods are well known to those skilled in the art and include, but arenot limited to, oral administration, transdermal administration,administration by inhalation, nasal administration, topicaladministration, intravaginal administration, ophthalmic administration,intraaural administration, intracerebral administration, rectaladministration, sublingual administration, buccal administration, andparenteral administration, including injectable such as intravenousadministration, intra-arterial administration, intramuscularadministration, and subcutaneous administration. Administration can becontinuous or intermittent. In various aspects, a preparation can beadministered therapeutically; that is, administered to treat an existingdisease or condition. In further various aspects, a preparation can beadministered prophylactically; that is, administered for prevention of adisease or condition.

As used herein, the terms “effective amount” and “amount effective”refer to an amount that is sufficient to achieve the desired result orto have an effect on an undesired condition. For example, a“therapeutically effective amount” refers to an amount that issufficient to achieve the desired therapeutic result or to have aneffect on undesired symptoms, but is generally insufficient to causeadverse side effects. The specific therapeutically effective dose levelfor any particular patient will depend upon a variety of factorsincluding the disorder being treated and the severity of the disorder;the specific composition employed; the age, body weight, general health,sex and diet of the patient; the time of administration; the route ofadministration; the rate of excretion of the specific compound employed;the duration of the treatment; drugs used in combination or coincidentalwith the specific compound employed and like factors well known in themedical arts. For example, it is well within the skill of the art tostart doses of a compound at levels lower than those required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved. If desired, the effective dailydose can be divided into multiple doses for purposes of administration.Consequently, single dose compositions can contain such amounts orsubmultiples thereof to make up the daily dose. The dosage can beadjusted by the individual physician in the event of anycontraindications. Dosage can vary, and can be administered in one ormore dose administrations daily, for one or several days. Guidance canbe found in the literature for appropriate dosages for given classes ofpharmaceutical products. In further various aspects, a preparation canbe administered in a “prophylactically effective amount”; that is, anamount effective for prevention of a disease or condition.

As used herein, “dosage form” means a pharmacologically active materialin a medium, carrier, vehicle, or device suitable for administration toa subject. A dosage form can comprise a disclosed compound, a product ofa disclosed method of making, or a salt, solvate, or polymorph thereof,in combination with a pharmaceutically acceptable excipient, such as apreservative, buffer, saline, or phosphate buffered saline. Dosage formscan be made using conventional pharmaceutical manufacturing andcompounding techniques. Dosage forms can comprise inorganic or organicbuffers (e.g., sodium or potassium salts of phosphate, carbonate,acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid,sodium or potassium hydroxide, salts of citrate or acetate, amino acidsand their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol),surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10nonyl phenol, sodium desoxycholate), solution and/or cryo/lyostabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmoticadjustment agents (e.g., salts or sugars), antibacterial agents (e.g.,benzoic acid, phenol, gentamicin), antifoaming agents (e.g.,polydimethylsilozone), preservatives (e.g., thimerosal,2-phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustmentagents (e.g., polyvinylpyrrolidone, poloxamer 488,carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethyleneglycol, ethanol). A dosage form formulated for injectable use can have adisclosed compound, a product of a disclosed method of making, or asalt, solvate, or polymorph thereof, suspended in sterile salinesolution for injection together with a preservative.

As used herein, “kit” means a collection of at least two componentsconstituting the kit. Together, the components constitute a functionalunit for a given purpose. Individual member components may be physicallypackaged together or separately. For example, a kit comprising aninstruction for using the kit may or may not physically include theinstruction with other individual member components. Instead, theinstruction can be supplied as a separate member component, either in apaper form or an electronic form which may be supplied on computerreadable memory device or downloaded from an internet website, or asrecorded presentation.

As used herein, “instruction(s)” means documents describing relevantmaterials or methodologies pertaining to a kit. These materials mayinclude any combination of the following: background information, listof components and their availability information (purchase information,etc.), brief or detailed protocols for using the kit, trouble-shooting,references, technical support, and any other related documents.Instructions can be supplied with the kit or as a separate membercomponent, either as a paper form or an electronic form which may besupplied on computer readable memory device or downloaded from aninternet website, or as recorded presentation. Instructions can compriseone or multiple documents, and are meant to include future updates.

As used herein, the terms “therapeutic agent” include any synthetic ornaturally occurring biologically active compound or composition ofmatter which, when administered to an organism (human or nonhumananimal), induces a desired pharmacologic, immunogenic, and/orphysiologic effect by local and/or systemic action. The term thereforeencompasses those compounds or chemicals traditionally regarded asdrugs, vaccines, and biopharmaceuticals including molecules such asproteins, peptides, hormones, nucleic acids, gene constructs and thelike. Examples of therapeutic agents are described in well-knownliterature references such as the Merck Index (14^(th) edition), thePhysicians' Desk Reference (64^(th) edition), and The PharmacologicalBasis of Therapeutics (12^(th) edition), and they include, withoutlimitation, medicaments; vitamins; mineral supplements; substances usedfor the treatment, prevention, diagnosis, cure or mitigation of adisease or illness; substances that affect the structure or function ofthe body, or pro-drugs, which become biologically active or more activeafter they have been placed in a physiological environment. For example,the term “therapeutic agent” includes compounds or compositions for usein all of the major therapeutic areas including, but not limited to,adjuvants; anti-infectives such as antibiotics and antiviral agents;analgesics and analgesic combinations, anorexics, anti-inflammatoryagents, anti-epileptics, local and general anesthetics, hypnotics,sedatives, antipsychotic agents, neuroleptic agents, antidepressants,anxiolytics, antagonists, neuron blocking agents, anticholinergic andcholinomimetic agents, antimuscarinic and muscarinic agents,antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, andnutrients, antiarthritics, antiasthmatic agents, anticonvulsants,antihistamines, antinauseants, antineoplastics, antipruritics,antipyretics; antispasmodics, cardiovascular preparations (includingcalcium channel blockers, beta-blockers, beta-agonists andantiarrhythmics), antihypertensives, diuretics, vasodilators; centralnervous system stimulants; cough and cold preparations; decongestants;diagnostics; hormones; bone growth stimulants and bone resorptioninhibitors; immunosuppressives; muscle relaxants; psychostimulants;sedatives; tranquilizers; proteins, peptides, and fragments thereof(whether naturally occurring, chemically synthesized or recombinantlyproduced); and nucleic acid molecules (polymeric forms of two or morenucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA)including both double- and single-stranded molecules, gene constructs,expression vectors, antisense molecules and the like), small molecules(e.g., doxorubicin) and other biologically active macromolecules suchas, for example, proteins and enzymes. The agent may be a biologicallyactive agent used in medical, including veterinary, applications and inagriculture, such as with plants, as well as other areas. The term“therapeutic agent” also includes without limitation, medicaments;vitamins; mineral supplements; substances used for the treatment,prevention, diagnosis, cure or mitigation of disease or illness; orsubstances which affect the structure or function of the body; orpro-drugs, which become biologically active or more active after theyhave been placed in a predetermined physiological environment.

The term “pharmaceutically acceptable” describes a material that is notbiologically or otherwise undesirable, i.e., without causing anunacceptable level of undesirable biological effects or interacting in adeleterious manner.

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

As used herein, the term “pharmaceutically acceptable carrier” refers tosterile aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, as well as sterile powders for reconstitution into sterileinjectable solutions or dispersions just prior to use. Examples ofsuitable aqueous and nonaqueous carriers, diluents, solvents or vehiclesinclude water, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol and the like), carboxymethylcellulose and suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of coating materials such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the use of surfactants. These compositions can also contain adjuvantssuch as preservatives, wetting agents, emulsifying agents and dispersingagents. Prevention of the action of microorganisms can be ensured by theinclusion of various antibacterial and antifungal agents such asparaben, chlorobutanol, phenol, sorbic acid and the like. It can also bedesirable to include isotonic agents such as sugars, sodium chloride andthe like. Prolonged absorption of the injectable pharmaceutical form canbe brought about by the inclusion of agents, such as aluminummonostearate and gelatin, which delay absorption. Injectable depot formsare made by forming microencapsule matrices of the drug in biodegradablepolymers such as polylactide-polyglycolide, poly(orthoesters) andpoly(anhydrides). Depending upon the ratio of drug to polymer and thenature of the particular polymer employed, the rate of drug release canbe controlled. Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues. The injectable formulations can be sterilized, forexample, by filtration through a bacterial-retaining filter or byincorporating sterilizing agents in the form of sterile solidcompositions which can be dissolved or dispersed in sterile water orother sterile injectable media just prior to use. Suitable inertcarriers can include sugars such as lactose. Desirably, at least 95% byweight of the particles of the active ingredient have an effectiveparticle size in the range of 0.01 to 10 micrometers.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, cycloalkyl, alkoxy, amino, ether, halide,hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A“lower alkyl” group is an alkyl group containing from one to six (e.g.,from one to four) carbon atoms. The term alkyl group can also be a C1alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl,C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up toand including a C1-C24 alkyl.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl”specifically refers to an alkyl group that is substituted with a singlehalide, e.g. fluorine, chlorine, bromine, or iodine. The term“polyhaloalkyl” specifically refers to an alkyl group that isindependently substituted with two or more halides, i.e. each halidesubstituent need not be the same halide as another halide substituent,nor do the multiple instances of a halide substituent need to be on thesame carbon. The term “alkoxyalkyl” specifically refers to an alkylgroup that is substituted with one or more alkoxy groups, as describedbelow. The term “aminoalkyl” specifically refers to an alkyl group thatis substituted with one or more amino groups. The term “hydroxyalkyl”specifically refers to an alkyl group that is substituted with one ormore hydroxy groups. When “alkyl” is used in one instance and a specificterm such as “hydroxyalkyl” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“hydroxyalkyl” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. For example,the cycloalkyl group and heterocycloalkyl group can be substituted with0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7cycloalkyl, C1-C4 alkoxy, —NH₂, (C1-C4) alkylamino, (C1-C4)(C1-C4)dialkylamino, ether, halogen, —OH, C1-C4 hydroxyalkyl, —NO₂, silyl,sulfo-oxo, —SH, and C1-C4 thioalkyl, as described herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Forexample, the cycloalkenyl group and heterocycloalkenyl group can besubstituted with 0, 1, 2, 3, or 4 groups independently selected fromC1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldeyhyde, —NH₂, (C1-C4)alkylamino, (C1-C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether,halogen, —OH, C1-C4 hydroxyalkyl, ketone, azide, —NO₂, silyl, sulfo-oxo,—SH, and C1-C4 thioalkyl, as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, anthracene, and the like. The aryl group can besubstituted or unsubstituted. The aryl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, —NH₂, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term“biaryl” is a specific type of aryl group and is included in thedefinition of “aryl.” In addition, the aryl group can be a single ringstructure or comprise multiple ring structures that are either fusedring structures or attached via one or more bridging groups such as acarbon-carbon bond. For example, biaryl can be two aryl groups that arebound together via a fused ring structure, as in naphthalene, or areattached via one or more carbon-carbon bonds, as in biphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” or “CO” is a short hand notationfor a carbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein. A specific example of amino is—NH₂.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula where A¹ and A² can be, independently, an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupdescribed herein and “a” is an integer of from 1 to 500. Examples ofpolyether groups include polyethylene oxide, polypropylene oxide, andpolybutylene oxide.

The terms “halo,” “halogen,” or “halide,” as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, 0, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The terms “heterocycle” or “heterocyclyl,” as used herein can be usedinterchangeably and refer to single and multi-cyclic aromatic ornon-aromatic ring systems in which at least one of the ring members isother than carbon. Thus, the term is inclusive of, but not limited to,“heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclicheterocycle.” Heterocycle includes pyridine, pyrimidine, furan,thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole,imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole,1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including,1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazoleand 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including1,2,4-triazine and 1,3,5-triazine, tetrazine, including1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine,azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. Theterm heterocyclyl group can also be a C2 heterocyclyl, C2-C3heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like upto and including a C2-C18 heterocyclyl. For example, a C2 heterocyclylcomprises a group which has two carbon atoms and at least oneheteroatom, including, but not limited to, aziridinyl, diazetidinyl,dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, forexample, a C5 heterocyclyl comprises a group which has five carbon atomsand at least one heteroatom, including, but not limited to, piperidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and thelike. It is understood that a heterocyclyl group may be bound eitherthrough a heteroatom in the ring, where chemically possible, or one ofcarbons comprising the heterocyclyl ring.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxy” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN or —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A¹S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A¹S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R′,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogen of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arethose that result in the formation of stable or chemically feasiblecompounds. In is also contemplated that, in certain aspects, unlessexpressly indicated to the contrary, individual substituents can befurther optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group are independently halogen;—(CH₂)₀₋₄R^(∘); —(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘)N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘); —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight orbranched)alkylene)O—N(R^(∘) ₂; or —(C₁₋₄ straight orbranched)alkylene)C(O)O—N(R^(∘) ₂, wherein each R^(∘) may be substitutedas defined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), are independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●), —(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●), —(CH₂)₀₋₂NR^(●) ₂,—NO₂, —C(O)SR^(●), —(C₁₋₄ straight or branched alkylene)C(O)OR^(●), or—SRR^(●) wherein each R^(●) is unsubstituted or where preceded by “halo”is substituted only with one or more halogens, and is independentlyselected from C₁₋₄ aliphatic, —CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur. Suitabledivalent substituents on a saturated carbon atom of R^(∘) include ═O and═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃O—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(●) include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) are independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, and brosylate.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has thestructure:

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthylradical. In some embodiments, an organic radical can contain 1-10inorganic heteroatoms bound thereto or therein, including halogens,oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organicradicals include but are not limited to an alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, mono-substituted amino,di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸ F and ³⁶Cl,respectively. Compounds further comprise prodrugs thereof, andpharmaceutically acceptable salts of said compounds or of said prodrugswhich contain the aforementioned isotopes and/or other isotopes of otheratoms are within the scope of this invention. Certainisotopically-labeled compounds of the present invention, for examplethose into which radioactive isotopes such as ³H and ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionassays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes areparticularly preferred for their ease of preparation and detectability.Further, substitution with heavier isotopes such as deuterium, i.e., ²H,can afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements and, hence, may be preferred in some circumstances.Isotopically labeled compounds of the present invention and prodrugsthereof can generally be prepared by carrying out the procedures below,by substituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvent orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et. al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andsupplemental volumes (Elsevier Science Publishers, 1989); OrganicReactions, Volumes 1-40 (John Wiley and Sons, 1991); March's AdvancedOrganic Chemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. COMPOUNDS

In one aspect, disclosed are compounds useful in treating or preventinga disorder associated with PanK activity such as, for example, PKAN anddiabetes. In a further aspect, the disclosed compounds exhibitmodulation of PanK activity. In a still further aspect, the disclosedcompounds exhibit inhibition of PanK activity. In yet a further aspect,the disclosed compounds exhibit activation of PanK activity.

In one aspect, the compounds of the invention are useful in thetreatment or prevention of disorders associated with PanK dysfunctionand other diseases in which PanKs or altered levels of CoA and CoAesters are involved, as further described herein.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods. It is also understood that the disclosed compounds can beemployed in the disclosed methods of using.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein Q² is a structure selected from:

wherein each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, provided at leastone of R^(3a), R^(3b), and R^(3c) is halogen; and wherein R⁴ is selectedform hydrogen, halogen, —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃, and NO₂, or apharmaceutically acceptable salt thereof.

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein A is selected from O, CO, CH₂, CF₂, NH, N(CH₃), and CH(OH);wherein each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, provided at leastone of R^(3a), R^(3b), and R^(3c) is halogen; and wherein R⁴ is selectedform hydrogen, halogen, —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃, and NO₂, or apharmaceutically acceptable salt thereof.

In a further aspect, the compound has a structure represented by aformula:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

In a further aspect, the compound is selected from:

a. A Groups

In one aspect, A is selected from O, CO, CH₂, CF₂, NH, N(CH₃), andCH(OH). In one aspect, A is selected from O, CO, CH₂, CF₂, NH, andCH(OH). In one aspect, O, CO, CH₂, CF₂, N(CH₃), and CH(OH). In oneaspect, A is selected from O, CO, CH₂, CF₂, and CH(OH).

In a further aspect, A is selected from O, CO, CH₂, and CF₂. In a stillfurther aspect, A is selected from O, CO, and CH₂. In yet a furtheraspect, A is selected from O and CO. In an even further aspect, A is O.In a still further aspect, A is CO. In yet a further aspect, A is CH₂.In an even further aspect, A is CF₂.

In a further aspect, A is selected from NH and N(CH₃). In a stillfurther aspect, A is NH. In yet a further aspect, A is N(CH₃).

In a further aspect, A is selected from NH and CH₂.

In a further aspect, A is CH(OH).

b. Q² Groups

In one aspect, Q² is a structure selected from:

In one aspect, Q² is a structure selected from:

In a further aspect, Q² is a structure selected from:

In a still further aspect, Q² is:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In a further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In a further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In an even further aspect, Q² is a structure selected from:

In a still further aspect, Q² is a structure selected from:

In yet a further aspect, Q² is a structure selected from:

In a further aspect, Q² is a structure:

C. R^(3A), R^(3B), and R^(3C) Groups

In one aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, providedat least one of R^(3a), R^(3b), and R^(3c) is halogen. In a furtheraspect, each of R^(3b) and R^(3c) is hydrogen. In a still furtheraspect, each of R^(3a) and R^(3c) is hydrogen. In yet a further aspect,each of R^(3a) and R^(3b) is hydrogen.

In a further aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen, —F, —Br, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, t-butyl, and s-butyl. In a still further aspect, eachof R^(3a), R^(3b), and R^(3c) is independently selected from hydrogen,—F, —Br, methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect,each of R^(3a), R^(3b), and R^(3c) is is independently selected fromhydrogen, —F, —Cl, —Br, methyl, and ethyl. In an even further aspect,each of R^(3a), R^(3b), and R^(3c) is independently selected fromhydrogen, —F, —Br, and methyl.

In a further aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen, —F, —Br, methyl, ethyl, n-propyl, i-propyl,—OCH₃, —OCH₂CH₃, —O(CH₂)₂CH₃, and —OCH(CH₃)₂. In a still further aspect,each of R^(3a), R^(3b), and R^(3c) is independently selected fromhydrogen, —F, —Cl, —Br, methyl, ethyl, —OCH₃, and —OCH₂CH₃. In yet afurther aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen, —F, —Br, methyl, and —OCH₃.

In a further aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen and C1-C4 alkyl. In a still further aspect, eachof R^(3a), R^(3b), and R^(3c) is independently selected from hydrogen,methyl, ethyl, n-propyl, and i-propyl. In yet a further aspect, each ofR^(3a), R^(3b), and R^(3c) is independently selected from hydrogen,methyl, and ethyl. In an even further aspect, each of R^(3a), R^(3b),and R^(3c) is independently selected from hydrogen and ethyl. In a stillfurther aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen and methyl.

In a further aspect, each of R^(3a), R^(3b), and R^(3c) is independentlyselected from hydrogen, —F, and —Br. In a still further aspect, each ofR^(3a), R^(3b), and R^(3c) is independently selected from hydrogen, —F,and —Cl. In yet a further aspect, each of R^(3a), R^(3b), and R^(3c) isindependently selected from hydrogen and —I. In an even further aspect,each of R^(3a), R^(3b), and R^(3c) is independently selected fromhydrogen and —Br. In a still further aspect, each of R^(3a), R^(3b), andR^(3c) is independently selected from hydrogen and —Cl. In yet a furtheraspect, each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen and —F.

In a further aspect, R^(3a) is halogen. In a still further aspect,R^(3a) is selected from —F, —Cl, and —Br. In yet a further aspect,R^(3a) is —F.

In a further aspect, R^(3a) is halogen and each of R^(3b) and R^(3c) ishydrogen. In a still further aspect, R^(3a) is selected from —F, —Cl,and —Br, and each of R^(3b) and R^(3c) is hydrogen. In yet a furtheraspect, R^(3a) is —F and each of R^(3b) and R^(3c) is hydrogen.

In a further aspect, R^(3b) is halogen. In a still further aspect,R^(3b) is selected from —F, —Cl, and —Br. In yet a further aspect,R^(3b) is —F.

In a further aspect, R^(3b) is halogen and each of R^(3a) and R^(3c) ishydrogen. In a still further aspect, R^(3b) is selected from —F, —Cl,and —Br, and each of R^(3a) and R^(3c) is hydrogen. In yet a furtheraspect, R^(3b) is —F and each of R^(3a) and R^(3c) is hydrogen.

In a further aspect, R^(3c) is halogen. In a still further aspect,R^(3c) is selected from —F, —Cl, and —Br. In yet a further aspect,R^(3c) is —F.

In a further aspect, R^(3c) is halogen and each of R^(3a) and R^(3b) ishydrogen. In a still further aspect, R^(3c) is selected from —F, —Cl,and —Br, and each of R^(3a) and R^(3b) is hydrogen. In yet a furtheraspect, R^(3c) is —F and each of R^(3a) and R^(3b) is hydrogen.

d. R⁴ Groups

In one aspect, R⁴ is selected from hydrogen, halogen, —CN, SO₂NH₂,SO₂CH₃, SO₂CF₃, and NO₂. In a further aspect, R⁴ is hydrogen.

In a further aspect, R⁴ is selected from —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃,and NO₂. In a still further aspect, R⁴ is selected from —CN, SO₂NH₂,SO₂CH₃, and SO₂CF₃. In yet a further aspect, R⁴ is selected from —CN,SO₂NH₂, and SO₂CH₃. In an even further aspect, R⁴ is selected from —CNand SO₂NH₂. In a still further aspect, R⁴ is NO₂. In yet a furtheraspect, R⁴ is SO₂CF₃. In an even further aspect, R⁴ is SO₂CH₃. In astill further aspect, R⁴ is SO₂NH₂. In yet a further aspect, R⁴ is —CN.

In a further aspect, R⁴ is selected from hydrogen and halogen. In astill further aspect, R⁴ is selected from hydrogen, —F, —Cl, and —Br. Inyet a further aspect, R⁴ is selected from hydrogen, —F, and —Cl. In aneven further aspect, R⁴ is selected from hydrogen and —I. In a stillfurther aspect, R⁴ is selected from hydrogen and —Br. In yet a furtheraspect, R⁴ is selected from hydrogen and —Cl. In an even further aspect,R⁴ is selected from hydrogen and —F.

In a further aspect, R⁴ is halogen. In a still further aspect, R⁴ isselected from —F, —Cl, and —Br. In yet a further aspect, R⁴ is selectedfrom —F and —Cl. In an even further aspect, R⁴ is —I. In a still furtheraspect, R⁴ is —Br. In yet a further aspect, R⁴ is —Cl. In an evenfurther aspect, R⁴ is —F.

2. Example Compounds

In one aspect, a compound can be present as one or more of the followingstructures:

or a pharmaceutically acceptable salt thereof.

In a further aspect, a compound can be present as one or more of thefollowing structures:

or a pharmaceutically acceptable salt thereof

3. Prophetic Compound Examples

The following compound examples are prophetic, and can be prepared usingthe synthesis methods described herein above and other general methodsas needed as would be known to one skilled in the art. It is anticipatedthat the prophetic compounds would be active as PanK antagonists, andsuch activity can be determined using the assay methods describedherein.

In one aspect, a compound can be selected from:

or a pharmaceutically acceptable derivative thereof.

C. METHODS OF MAKING A COMPOUND

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Routes I-VI, as described andexemplified below. The following examples are provided so that theinvention might be more fully understood, are illustrative only, andshould not be construed as limiting.

1. Route I

In one aspect, substituted small molecule modulators of PanK can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein; wherein X is halogen. A morespecific example is set forth below.

In one aspect, compounds of type 1.7, and similar compounds, can beprepared according to reaction Scheme 1B above. Thus, compounds of type1.7 are either commercially available or can be prepared by an arylationreaction of an appropriate amine, e.g., 1.1 as shown above, and anappropriate aryl halide, e.g., 1.6 as shown above. Appropriate aminesand appropriate aryl halides are commercially available or prepared bymethods known to one skilled in the art. The arylation reaction iscarried out in the presence of an appropriate base, e.g., triethylamine(TEA), in an appropriate solvent, e.g., acetonitrile, at an appropriatetemperature, e.g., 160° C., for an appropriate period of time, e.g., 30minutes using microwave irradiation. The arylation reaction is followedby a deprotection. The deprotection is carried out in the presence of anappropriate deprotecting agent, e.g., trifluoroacetic acid (TFA), in anappropriate solvent, e.g., dichloromethane, for an appropriate period oftime, e.g., 1 hour. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.1 and 1.2), can be substitutedin the reaction to provide substituted small molecule modulators of PanKsimilar to Formula 1.3.

2. Route II

In one aspect, substituted small molecule modulators of PanK can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein and wherein A is selected fromCH₂, CF₂, and CH(OH). A more specific example is set forth below.

In one aspect, compounds of type 2.6, and similar compounds, can beprepared according to reaction Scheme 2B above. Thus, compounds of type2.6 can be prepared by a coupling reaction of an appropriate carboxylicacid, e.g., 2.4 as shown above, with an appropriate amine, e.g., 2.5 asshown above. Appropriate carboxylic acids and appropriate amines arecommercially available or prepared by methods known to one skilled inthe art. The coupling reaction is carried out in the presence of anappropriate coupling agent, e.g.,1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU), and an appropriate base, e.g.,diisopropylethylamine (DIPEA), in an appropriate solvent, e.g.,dichloromethane. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 2.1 and 2.2), can be substitutedin the reaction to provide substituted small molecule modulators of PanKsimilar to Formula 2.3.

3. Route III

In one aspect, substituted small molecule modulators of PanK can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein and wherein X is halogen. A morespecific example is set forth below.

In one aspect, compounds of type 3.12, and similar compounds, can beprepared according to reaction Scheme 3B above. Thus, compounds of type3.2 can be prepared by a coupling reaction of an appropriate amine,e.g., 3.1 as shown above. Appropriate amines are commercially availableor prepared by methods known to one skilled in the art. The couplingreaction is carried out in the presence of an appropriate couplingagent, e.g., N,N-carbonyldiimidazole (CDI), in an appropriate solvent,e.g., dichloromethane. Compounds of type 3.9 can be prepared by areaction of an appropriate activated-urea, e.g., 3.2, and an appropriatephenol, e.g., 3.8 as shown above. Appropriate phenols are commerciallyavailable or prepared by methods known to one skilled in the art. Thereaction is carried out in the presence of an appropriate base, e.g.,triethylamine and cesium carbonate, in an appropriate solvent, e.g.,acetonitrile, at an appropriate temperature, e.g., 70° C., for anappropriate period of time, e.g., 3-4 hours or overnight. Compounds oftype 3.10 can be prepared by a deprotection reaction of an appropriatepiperazine, e.g., 3.9 as shown above. The deprotection reaction iscarried out in the presence of an appropriate deprotecting agent, e.g.,trifluoroacetic acid, and an appropriate solvent, e.g., dichloromethane,for an appropriate period of time, e.g., 2 hours. Compounds of type 3.12can be prepared by an arylation reaction of an appropriate amine, e.g.,3.10 as shown above, and an appropriate aryl halide, e.g., 3.11 as shownabove. Appropriate aryl halides are commercially available or preparedby methods known to one skilled in the art. The arylation reaction iscarried out in the presence of an appropriate base, e.g., triethylamine,and an appropriate solvent, e.g., acetonitrile, at an appropriatetemperature, e.g., 160° C., for an appropriate period of time, e.g., 30minutes using microwave irradiations. As can be appreciated by oneskilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 3.1,3.2, 3.3, 3.4, 3.5, and 3.6), can be substituted in the reaction toprovide substituted small molecule modulators of PanK similar to Formula3.7.

4. Route IV

In one aspect, substituted small molecule modulators of PanK can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein and wherein X is halogen. A morespecific example is set forth below.

In one aspect, compounds of type 4.8, and similar compounds, can beprepared according to reaction Scheme 4B above. Thus, compounds of type4.6 can be prepared by a urea bond formation reaction between anappropriate amine, e.g., 4.2 as shown above, and an appropriateisocyanate, e.g., 4.5 as shown above. Appropriate amines and appropriateisocyanates are commercially available or prepared by methods known toone skilled in the art. The nucleophilic substitution is carried out inthe presence of an appropriate solvent, e.g., diethyl ether, for anappropriate period of time, e.g., 3 hours. The nucleophilic substitutionis followed by a deprotection reaction. The deprotection reaction iscarried out in the presence of an appropriate deprotecting agent, e.g.,trifluoroacetic acid, in an appropriate solvent, e.g., dichloromethane,for an appropriate period of time, e.g., 1 hour. Compounds of type 4.8can be prepared by an arylation reaction of appropriate amine, e.g., 4.6as shown above, and an appropriate aryl halide, e.g., 4.7 as shownabove. Appropriate aryl halides are commercially available or preparedby methods known to one skilled in the art. The arylation reaction iscarried out in the presence of an appropriate base, e.g., triethylamine,in an appropriate solvent, e.g., acetonitrile, at an appropriatetemperature, e.g, 160° C., for an appropriate period of time, e.g., 30minutes using microwave irradiations. As can be appreciated by oneskilled in the art, the above reaction provides an example of ageneralized approach wherein compounds similar in structure to thespecific reactants above (compounds similar to compounds of type 3.6,4.1, 4.2, and 4.3), can be substituted in the reaction to provide4-aryl-N-phenylpiperazine-1-carboxamide derivatives similar to Formula4.4.

5. Route V

In one aspect, substituted small molecule modulators of PanK can beprepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein and wherein X is halogen. A morespecific example is set forth below.

In one aspect, compounds of type 5.6, and similar compounds, can beprepared according to reaction Scheme 5B above. Thus, compounds of type5.5 can be prepared by a coupling reaction of an appropriate amine,e.g., 4.2 as shown above, and an appropriate carboxylic acid, e.g., 5.4as shown above. Appropriate amines and appropriate carboxylic acids arecommercially available or prepared by methods known to one skilled inthe art. The coupling reaction is carried out in the presence of anappropriate coupling agent, e.g., HATU, and an appropriate base, e.g.,DIPEA, in an appropriate solvent, e.g., dichloromethane. The couplingreaction is followed by a deprotection reaction. The deprotectionreaction is carried out in the presence of an appropriate deprotectingagent, e.g., trifluoroacetic acid, in an appropriate solvent, e.g.,dichloromethane, for an appropriate period of time, e.g., 1 hour.Compounds of type 5.6 can be prepared by an arylation reaction of anappropriate amine, e.g., 5.5, and an appropriate aryl halide, e.g., 3.11as shown above. Appropriate aryl halides are commercially available orprepared by methods known to one skilled in the art. The arylationreaction is carried out in the presence of an appropriate base, e.g.,triethylamine, in an appropriate solvent, e.g., acetonitrile, at anappropriate temperature, e.g., 160° C., for an appropriate period oftime, e.g., 30 minutes using microwave irradiations. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type3.6, 4.2, 5.1, and 5.2), can be substituted in the reaction to providesubstituted small molecule modulators of PanK similar to Formula 5.3.

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

D. PHARMACEUTICAL COMPOSITIONS

In one aspect, disclosed are pharmaceutical compositions comprising adisclosed compound, or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

In various aspects, the compounds and compositions of the invention canbe administered in pharmaceutical compositions, which are formulatedaccording to the intended method of administration. The compounds andcompositions described herein can be formulated in a conventional mannerusing one or more physiologically acceptable carriers or excipients. Forexample, a pharmaceutical composition can be formulated for local orsystemic administration, e.g., administration by drops or injection intothe ear, insufflation (such as into the ear), intravenous, topical, ororal administration.

The nature of the pharmaceutical compositions for administration isdependent on the mode of administration and can readily be determined byone of ordinary skill in the art. In various aspects, the pharmaceuticalcomposition is sterile or sterilizable. The therapeutic compositionsfeatured in the invention can contain carriers or excipients, many ofwhich are known to skilled artisans. Excipients that can be used includebuffers (for example, citrate buffer, phosphate buffer, acetate buffer,and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid,phospholipids, polypeptides (for example, serum albumin), EDTA, sodiumchloride, liposomes, mannitol, sorbitol, water, and glycerol. Thenucleic acids, polypeptides, small molecules, and other modulatorycompounds featured in the invention can be administered by any standardroute of administration. For example, administration can be parenteral,intravenous, subcutaneous, or oral. A modulatory compound can beformulated in various ways, according to the corresponding route ofadministration. For example, liquid solutions can be made foradministration by drops into the ear, for injection, or for ingestion;gels or powders can be made for ingestion or topical application.Methods for making such formulations are well known and can be found in,for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro,ed., Mack Publishing Co., Easton, Pa. 1990.

In various aspects, the disclosed pharmaceutical compositions comprisethe disclosed compounds (including pharmaceutically acceptable salt(s)thereof) as an active ingredient, a pharmaceutically acceptable carrier,and, optionally, other therapeutic ingredients or adjuvants. The instantcompositions include those suitable for oral, rectal, topical, andparenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions can be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy.

In various aspects, the pharmaceutical compositions of this inventioncan include a pharmaceutically acceptable carrier and a compound or apharmaceutically acceptable salt of the compounds of the invention. Thecompounds of the invention, or pharmaceutically acceptable saltsthereof, can also be included in pharmaceutical compositions incombination with one or more other therapeutically active compounds.

The pharmaceutical carrier employed can be, for example, a solid,liquid, or gas. Examples of solid carriers include lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, andstearic acid. Examples of liquid carriers are sugar syrup, peanut oil,olive oil, and water. Examples of gaseous carriers include carbondioxide and nitrogen.

In preparing the compositions for oral dosage form, any convenientpharmaceutical media can be employed. For example, water, glycols, oils,alcohols, flavoring agents, preservatives, coloring agents and the likecan be used to form oral liquid preparations such as suspensions,elixirs and solutions; while carriers such as starches, sugars,microcrystalline cellulose, diluents, granulating agents, lubricants,binders, disintegrating agents, and the like can be used to form oralsolid preparations such as powders, capsules and tablets. Because oftheir ease of administration, tablets and capsules are the preferredoral dosage units whereby solid pharmaceutical carriers are employed.Optionally, tablets can be coated by standard aqueous or nonaqueoustechniques

A tablet containing the composition of this invention can be prepared bycompression or molding, optionally with one or more accessoryingredients or adjuvants. Compressed tablets can be prepared bycompressing, in a suitable machine, the active ingredient in afree-flowing form such as powder or granules, optionally mixed with abinder, lubricant, inert diluent, surface active or dispersing agent.Molded tablets can be made by molding in a suitable machine, a mixtureof the powdered compound moistened with an inert liquid diluent.

The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof)as an active ingredient, a pharmaceutically acceptable carrier, andoptionally one or more additional therapeutic agents or adjuvants. Theinstant compositions include compositions suitable for oral, rectal,topical, and parenteral (including subcutaneous, intramuscular, andintravenous) administration, although the most suitable route in anygiven case will depend on the particular host, and nature and severityof the conditions for which the active ingredient is being administered.The pharmaceutical compositions can be conveniently presented in unitdosage form and prepared by any of the methods well known in the art ofpharmacy.

Pharmaceutical compositions of the present invention suitable forparenteral administration can be prepared as solutions or suspensions ofthe active compounds in water. A suitable surfactant can be includedsuch as, for example, hydroxypropylcellulose. Dispersions can also beprepared in glycerol, liquid polyethylene glycols, and mixtures thereofin oils. Further, a preservative can be included to prevent thedetrimental growth of microorganisms.

Pharmaceutical compositions of the present invention suitable forinjectable use include sterile aqueous solutions or dispersions.Furthermore, the compositions can be in the form of sterile powders forthe extemporaneous preparation of such sterile injectable solutions ordispersions. In all cases, the final injectable form must be sterile andmust be effectively fluid for easy syringability. The pharmaceuticalcompositions must be stable under the conditions of manufacture andstorage; thus, preferably should be preserved against the contaminatingaction of microorganisms such as bacteria and fungi. The carrier can bea solvent or dispersion medium containing, for example, water, ethanol,polyol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), vegetable oils, and suitable mixtures thereof.

Pharmaceutical compositions of the present invention can be in a formsuitable for topical use such as, for example, an aerosol, cream,ointment, lotion, dusting powder, mouth washes, gargles, and the like.Further, the compositions can be in a form suitable for use intransdermal devices. These formulations can be prepared, utilizing acompound of the invention, or pharmaceutically acceptable salts thereof,via conventional processing methods. As an example, a cream or ointmentis prepared by mixing hydrophilic material and water, together withabout 5 wt % to about 10 wt % of the compound, to produce a cream orointment having a desired consistency.

Pharmaceutical compositions of this invention can be in a form suitablefor rectal administration wherein the carrier is a solid. It ispreferable that the mixture forms unit dose suppositories. Suitablecarriers include cocoa butter and other materials commonly used in theart. The suppositories can be conveniently formed by first admixing thecomposition with the softened or melted carrier(s) followed by chillingand shaping in molds.

In addition to the aforementioned carrier ingredients, thepharmaceutical formulations described above can include, as appropriate,one or more additional carrier ingredients such as diluents, buffers,flavoring agents, binders, surface-active agents, thickeners,lubricants, preservatives (including anti-oxidants) and the like.Furthermore, other adjuvants can be included to render the formulationisotonic with the blood of the intended recipient. Compositionscontaining a compound of the invention, and/or pharmaceuticallyacceptable salts thereof, can also be prepared in powder or liquidconcentrate form.

In a further aspect, an effective amount is a therapeutically effectiveamount. In a still further aspect, an effective amount is aprophylactically effective amount.

In a further aspect, the pharmaceutical composition is administered to amammal. In a still further aspect, the mammal is a human. In an evenfurther aspect, the human is a patient.

In a further aspect, the pharmaceutical composition is used to treat adisorder associated with pantothenate kinase activity such as, forexample, PKAN and diabetes.

It is understood that the disclosed compositions can be prepared fromthe disclosed compounds. It is also understood that the disclosedcompositions can be employed in the disclosed methods of using.

E. METHODS OF TREATING A DISORDER ASSOCIATED WITH PANK ACTIVITY

In various aspects, the compounds and compositions disclosed herein areuseful for treating, preventing, ameliorating, controlling or reducingthe risk of a variety of disorders associated with pantothenate kinaseactivity, including, for example, PKAN, aging and diabetes. Thus, in oneaspect, disclosed are methods of treating a disorder associated withpantothenate kinase activity in a subject, the method comprisingadministering to the subject an effective amount of at least onedisclosed compound or a pharmaceutically acceptable salt thereof.

In various aspects, the disclosed compounds can be used in combinationwith one or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of disorders associated with PanKactivity for which disclosed compounds or the other drugs can haveutility, where the combination of the drugs together are safer or moreeffective than either drug alone. Such other drug(s) can beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and adisclosed compound is preferred. However, the combination therapy canalso include therapies in which a disclosed compound and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the disclosed compounds and the other activeingredients can be used in lower doses than when each is used singly.Accordingly, the pharmaceutical compositions include those that containone or more other active ingredients, in addition to a compound of thepresent invention.

In a further aspect, the compound exhibits inhibition of PanK activity.In a still further aspect, the compound exhibits a decrease in PanKactivity.

In a further aspect, the compound exhibits inhibition of PanK activitywith an IC₅₀ of from about 0.001 μM to about 25 μM. In a still furtheraspect, the compound exhibits inhibition of PanK activity with an IC₅₀of from about 0.001 μM to about 15 μM. In yet a further aspect, thecompound exhibits inhibition of PanK activity with an IC₅₀ of from about0.001 μM to about 10 μM. In an even further aspect, the compoundexhibits inhibition of PanK activity with an IC₅₀ of from about 0.001 μMto about 5 μM. In a still further aspect, the compound exhibitsinhibition of PanK activity with an IC₅₀ of from about 0.001 μM to about1 μM. In yet a further aspect, the compound exhibits inhibition of PanKactivity with an IC₅₀ of from about 0.001 μM to about 0.5 μM. In an evenfurther aspect, the compound exhibits inhibition of PanK activity withan IC₅₀ of from about 0.001 μM to about 0.1 μM. In a still furtheraspect, the compound exhibits inhibition of PanK activity with an IC₅₀of from about 0.001 μM to about 0.05 μM. In yet a further aspect, thecompound exhibits inhibition of PanK activity with an IC₅₀ of from about0.001 μM to about 0.01 μM. In an even further aspect, the compoundexhibits inhibition of PanK activity with an IC₅₀ of from about 0.001 μMto about 0.005 μM. In a still further aspect, the compound exhibitsinhibition of PanK activity with an IC₅₀ of from about 0.005 μM to about25 μM. In yet a further aspect, the compound exhibits inhibition of PanKactivity with an IC₅₀ of from about 0.01 μM to about 25 μM. In an evenfurther aspect, the compound exhibits inhibition of PanK activity withan IC₅₀ of from about 0.05 μM to about 25 μM. In a still further aspect,the compound exhibits inhibition of PanK activity with an IC₅₀ of fromabout 0.1 μM to about 25 μM. In yet a further aspect, the compoundexhibits inhibition of PanK activity with an IC₅₀ of from about 0.5 μMto about 25 μM. In an even further aspect, the compound exhibitsinhibition of PanK activity with an IC₅₀ of from about 1 μM to about 25μM. In a still further aspect, the compound exhibits inhibition of PanKactivity with an IC₅₀ of from about 5 μM to about 25 μM. In yet afurther aspect, the compound exhibits inhibition of PanK activity withan IC₅₀ of from about 10 μM to about 25 μM. In an even further aspect,the compound exhibits inhibition of PanK activity with an IC₅₀ of fromabout 15 μM to about 25 μM.

In a further aspect, the subject is a mammal. In a still further aspect,the mammal is human.

In a further aspect, the subject has been diagnosed with a need fortreatment of the disorder prior to the administering step. In a stillfurther aspect, the subject is at risk for developing the disorder priorto the administering step.

In a further aspect, the method further comprises identifying a subjectat risk for developing the disorder prior to the administering step.

F. METHODS OF MODULATING PANK ACTIVITY IN AT LEAST ONE CELL

In one aspect, disclosed are methods of modulating pantothenate kinaseactivity in at least one cell, the method comprising the step ofcontacting the at least one cell with an effective amount of at leastone disclosed compound, or a pharmaceutically acceptable salt thereof.In a further aspect, modulating is inhibiting.

In a further aspect, the cell is mammalian. In a still further aspect,the cell is human. In yet a further aspect, the cell has been isolatedfrom a mammal prior to the contacting step.

In a further aspect, contacting is via administration to a mammal.

G. METHODS OF USING THE COMPOSITIONS

Provided are methods of using of a disclosed composition or medicament.In one aspect, the method of use is directed to the treatment of adisorder. In a further aspect, the disclosed compounds can be used assingle agents or in combination with one or more other drugs in thetreatment, prevention, control, amelioration, or reduction of risk ofthe aforementioned diseases, disorders and conditions for which thecompound or the other drugs have utility, where the combination of drugstogether are safer or more effective than either drug alone. The otherdrug(s) can be administered by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a disclosed compound.When a disclosed compound is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch drugs and the disclosed compound is preferred. However, thecombination therapy can also be administered on overlapping schedules.It is also envisioned that the combination of one or more activeingredients and a disclosed compound can be more efficacious than eitheras a single agent.

The pharmaceutical compositions and methods of the present invention canfurther comprise other therapeutically active compounds as noted hereinwhich are usually applied in the treatment of the above mentionedpathological conditions.

1. Manufacture of a Medicament

In one aspect, the invention relates to a method for the manufacture ofa medicament for treating a disorder associated with PanK dysfunction ina mammal, the method comprising combining a therapeutically effectiveamount of a disclosed compound or product of a disclosed method with apharmaceutically acceptable carrier or diluent.

As regards these applications, the present method includes theadministration to an animal, particularly a mammal, and moreparticularly a human, of a therapeutically effective amount of thecompound effective in the inhibition of protein and especially PanK. Thedose administered to an animal, particularly a human, in the context ofthe present invention should be sufficient to affect a therapeuticresponse in the animal over a reasonable time frame. One skilled in theart will recognize that dosage will depend upon a variety of factorsincluding the condition of the animal, the body weight of the animal, aswell as the severity and stage of the disorder.

Thus, in one aspect, the invention relates to the manufacture of amedicament comprising combining a disclosed compound or a product of adisclosed method of making, or a pharmaceutically acceptable salt,solvate, or polymorph thereof, with a pharmaceutically acceptablecarrier or diluent.

2. Use of Compounds and Compositions

Also provided are the uses of the disclosed compounds and compositions.Thus, in one aspect, the invention relates to the uses of modulators ofPanK.

In a further aspect, the invention relates to the use of a disclosedcompound or product of a disclosed method in the manufacture of amedicament for the treatment of a disorder associated with PanK activityand associated Coenzyme A levels such as, for example, PKAN anddiabetes.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method, and apharmaceutically acceptable carrier, for use as a medicament.

In a further aspect, the use relates to a process for preparing apharmaceutical composition comprising a therapeutically effective amountof a disclosed compound or a product of a disclosed method, wherein apharmaceutically acceptable carrier is intimately mixed with atherapeutically effective amount of the disclosed compound or theproduct of a disclosed method.

In various aspects, the use relates to the treatment of PKAN in avertebrate animal. In a further aspect, the use relates to the treatmentof PKAN in a human subject.

In a further aspect, the use is the treatment of diabetes. In a stillfurther aspect, the diabetes is type II diabetes.

It is understood that the disclosed uses can be employed in connectionwith the disclosed compounds, methods, compositions, and kits. In afurther aspect, the invention relates to the use of a disclosed compoundor composition of a medicament for the treatment of a disorderassociated with PanK activity in a mammal.

In a further aspect, the invention relates to the use of a disclosedcompound or composition in the manufacture of a medicament for thetreatment of a disorder associated with PanK activity selected from PKANand diabetes.

3. Kits

In one aspect, disclosed are kits comprising a disclosed compound andone or more of: (a) at least one agent known to treat PKAN; (b) at leastone agent known to treat diabetes; (c) instructions for treating PKAN;and (d) instructions for treating diabetes, metabolic syndrome, and/orside effects of aging.

In various aspects, the agents and pharmaceutical compositions describedherein can be provided in a kit. The kit can also include combinationsof the agents and pharmaceutical compositions described herein.

In various aspects, the informational material can be descriptive,instructional, marketing or other material that relates to the methodsdescribed herein and/or to the use of the agents for the methodsdescribed herein. For example, the informational material may relate tothe use of the agents herein to treat a subject who has, or who is atrisk for developing, a disorder associated with PanK activity. The kitscan also include paraphernalia for administering the agents of thisinvention to a cell (in culture or in vivo) and/or for administering acell to a patient.

In various aspects, the informational material can include instructionsfor administering the pharmaceutical composition and/or cell(s) in asuitable manner to treat a human, e.g., in a suitable dose, dosage form,or mode of administration (e.g., a dose, dosage form, or mode ofadministration described herein). In a further aspect, the informationalmaterial can include instructions to administer the pharmaceuticalcomposition to a suitable subject, e.g., a human having, or at risk fordeveloping, a disorder associated with PanK activity.

In various aspects, the composition of the kit can include otheringredients, such as a solvent or buffer, a stabilizer, a preservative,a fragrance or other cosmetic ingredient. In such aspects, the kit caninclude instructions for admixing the agent and the other ingredients,or for using one or more compounds together with the other ingredients.

In a further aspect, the compound and the at least one agent known totreat PKAN are co-formulated. In a still further aspect, the compoundand the at least one agent known to treat PKAN are co-packaged.

In a further aspect, the compound and the at least one agent known totreat diabetes are co-formulated. In a still further aspect, thecompound and the at least one agent known to treat diabetes areco-packaged.

In a further aspect, the at least one agent known to treat PKAN isselected from baclofen, trihexyphenidyl, botulinum toxin, and an ironchelating agent. In a still further aspect, the iron chelating agent isdeferriprone.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of the compound and the at least one agentknown to treat PKAN. In a still further aspect, the effective amount isa therapeutically effective amount. In yet a further aspect, theeffective amount is a prophylactically effective amount. In an evenfurther aspect, each dose of the compound and at least one agent knownto treat PKAN are co-packaged. In a still further aspect, each dose ofthe compound and the at least one agent known to treat PKAN areco-formulated.

In a further aspect, the at least one agent known to treat diabetes isselected from insulin, albiglutide, exenatide, liraglutide, pramlintide,dulaglutide, acarbose, alogliptin, bromocriptine mesylate,canagliflozin, chlorpropamide, colesevelam, dapagliflozin,empagliflozin, glimepiride, glipizide, glyburide, linagliptin,metformin, miglitol, nateglinide, pioglitazone, repaglinide,rosiglitazone, saxagliptin, and sitagliptin.

In a further aspect, the kit further comprises a plurality of dosageforms, the plurality comprising one or more doses; wherein each dosecomprises an effective amount of the compound and at least one agentknown to treat diabetes. In a still further aspect, the effective amountis a therapeutically effective amount. In yet a further aspect, theeffective amount is a prophylactically effective amount. In an evenfurther aspect, each dose of the compound and at least one agent knownto treat diabetes are co-packaged. In a still further aspect, each doseof the compound and at least one agent known to treat diabetes areco-formulated.

4. Subjects

In various aspects, the subject of the herein disclosed methods is avertebrate, e.g., a mammal. Thus, the subject of the herein disclosedmethods can be a human, non-human primate, horse, pig, rabbit, dog,sheep, goat, cow, cat, guinea pig or rodent. The term does not denote aparticular age or sex. Thus, adult and newborn subjects, as well asfetuses, whether male or female, are intended to be covered. A patientrefers to a subject afflicted with a disease or disorder. The term“patient” includes human and veterinary subjects.

In some aspects of the disclosed methods, the subject has been diagnosedwith a need for treatment prior to the administering step. In someaspects of the disclosed method, the subject has been diagnosed with adisorder associated with PanK activity prior to the administering step.In some aspects of the disclosed methods, the subject has beenidentified with a need for treatment prior to the administering step. Inone aspect, a subject can be treated prophylactically with a compound orcomposition disclosed herein, as discussed herein elsewhere.

a. Dosage

Toxicity and therapeutic efficacy of the agents and pharmaceuticalcompositions described herein can be determined by standardpharmaceutical procedures, using either cells in culture or experimentalanimals to determine the LD₅₀ (the dose lethal to 50% of the population)and the ED₅₀ (the dose therapeutically effective in 50% of thepopulation). The dose ratio between toxic and therapeutic effects is thetherapeutic index and can be expressed as the ratio LD₅₀/ED₅₀.Polypeptides or other compounds that exhibit large therapeutic indicesare preferred.

Data obtained from cell culture assays and further animal studies can beused in formulating a range of dosage for use in humans. The dosage ofsuch compounds lies preferably within a range of circulatingconcentrations that include the ED₅₀ with little or no toxicity, andwith little or no adverse effect on a human's ability to hear. Thedosage may vary within this range depending upon the dosage formemployed and the route of administration utilized. For any agents usedin the methods described herein, the therapeutically effective dose canbe estimated initially from cell culture assays. A dose can beformulated in animal models to achieve a circulating plasmaconcentration range that includes the IC₅₀ (that is, the concentrationof the test compound which achieves a half-maximal inhibition ofsymptoms) as determined in cell culture. Such information can be used tomore accurately determine useful doses in humans. Exemplary dosageamounts of a differentiation agent are at least from about 0.01 to 3000mg per day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1,2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day,or more.

The formulations and routes of administration can be tailored to thedisease or disorder being treated, and for the specific human beingtreated. For example, a subject can receive a dose of the agent once ortwice or more daily for one week, one month, six months, one year, ormore. The treatment can continue indefinitely, such as throughout thelifetime of the human. Treatment can be administered at regular orirregular intervals (once every other day or twice per week), and thedosage and timing of the administration can be adjusted throughout thecourse of the treatment. The dosage can remain constant over the courseof the treatment regimen, or it can be decreased or increased over thecourse of the treatment.

In various aspects, the dosage facilitates an intended purpose for bothprophylaxis and treatment without undesirable side effects, such astoxicity, irritation or allergic response. Although individual needs mayvary, the determination of optimal ranges for effective amounts offormulations is within the skill of the art. Human doses can readily beextrapolated from animal studies (Katocs et al., (1990) Chapter 27 inRemington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., MackPublishing Co., Easton, Pa.). In general, the dosage required to providean effective amount of a formulation, which can be adjusted by oneskilled in the art, will vary depending on several factors, includingthe age, health, physical condition, weight, type and extent of thedisease or disorder of the recipient, frequency of treatment, the natureof concurrent therapy, if required, and the nature and scope of thedesired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman'sThe Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al.,eds., McGraw-Hill, New York, N.Y.).

b. Routes of Administration

Also provided are routes of administering the disclosed compounds andcompositions. The compounds and compositions of the present inventioncan be administered by direct therapy using systemic administrationand/or local administration. In various aspects, the route ofadministration can be determined by a patient's health care provider orclinician, for example following an evaluation of the patient. Invarious aspects, an individual patient's therapy may be customized,e.g., the type of agent used, the routes of administration, and thefrequency of administration can be personalized. Alternatively, therapymay be performed using a standard course of treatment, e.g., usingpre-selected agents and pre-selected routes of administration andfrequency of administration.

Systemic routes of administration can include, but are not limited to,parenteral routes of administration, e.g., intravenous injection,intramuscular injection, and intraperitoneal injection; enteral routesof administration e.g., administration by the oral route, lozenges,compressed tablets, pills, tablets, capsules, drops (e.g., ear drops),syrups, suspensions and emulsions; rectal administration, e.g., a rectalsuppository or enema; a vaginal suppository; a urethral suppository;transdermal routes of administration; and inhalation (e.g., nasalsprays).

In various aspects, the modes of administration described above may becombined in any order.

H. EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Chemistry Experimentals

A. General Synthesis Procedures

i. Method A:6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)pyridazine-3-carbonitrile

To a cold (ice), stirred mixture of2-(4-cyclopropyl-3-fluorophenyl)acetic acid (150 mg, 0.772 mmol),4-(6-cyanopyridazin-3-yl)piperazin-1-ium chloride (218 mg, 0.850 mmol,88%), and HATU (382 mg, 1.0 mmol) in DMF (3.0 mL) was added neat DIPA(404 μL, 2.32 mmol). The mixture was warmed to rt, stirred for 16 hours,and then heated at 50° C. for 1 hour. Next, the mixture was cooled tort, diluted with water (10 mL), and extracted with ethyl acetate (2×15mL). The combined extracts were washed with aq. 1N HCl, bicarbonatesolution, and brine, dried over Na₂SO₄, and concentrated. The residuewas purified on a 25 g SiO₂ cartridge using a gradient of ethyl acetatein hexanes (50% to 100%, and 100%) to afford the title compound (160 mg,56.7%) as a beige solid. Rf=0.25 (EtOAc).

ii. Method B:6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)pyridazine-3-carbonitrile

To a cold (ice), stirred mixture of2-(4-cyclopropyl-3-fluorophenyl)acetic acid (3.35 g, 17.2 mmol) and1-(6-cyanopyridazin-3-yl)piperazine-1,4-diium chloride (4.97 g, 19.0mmol) in DMF (35 mL) was added a 50% solution of propylphosphonicanhydride (13.3 mL, 22.4 mmol) in DMF, followed by the addition of neatDIPA (13.8 mL, 79.3 mmol). The reaction mixture was slowly warmed to rtand stirred for 17 hours. Next, the reaction was slowly quenched withwater (100 mL) (slightly exothermic) and stirred for 10 min before beingfiltered off using a Buchner funnel, washed with water (500 mL), anddried under high vacuum to afford 6-(4-(2-(4-cyclopropyl-3fluorophenyl)acetyl)piperazin-1-yl)pyridazine-3-carbonitrile (5.95 g,94.4%) as an off-white solid. The purity of this product is greater than95%. The product (4.77 g) was added in a mixture of MeOH-EtOAc (1:1, 100mL). The suspension was then heated at 80° C. for 10 min to reach aclear, pale yellow solution. The solution was filtered out and thefiltrate was kept at room temperature for 24 hours. The solid wasfiltered, rinsed with EtOAc (10 mL), and dried to afford6-(4-(2-(4-cyclopropyl-3-fluorophenypacetyppiperazin-1-yl)pyridazine-3-carbonitrile(3.65 g, 76.5%) as an off-white solid. HPLC purity, >99.9%.

b. Spectral Data of Exemplary Compounds

i. Example 1:6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)piperazin-1-yl)pyridazine-3-carbonitrile

¹H NMR (600 MHz, CDCl₃) δ 7.50 (d, J=9.6 Hz, 1H), 6.96-6.95 (m, 1H),6.94 (s, 1H), 6.88 (t, J=7.9 Hz, 1H), 6.85 (d, J=9.6 Hz, 1H), 3.87-3.82(m, 2H), 3.82-3.78 (m, 2H), 3.76 (s, 2H), 3.74-3.70 (m, 2H), 3.67-3.63(m, 2H), 2.11-2.02 (m, 1H), 1.02-0.96 (m, 2H), 0.75-0.69 (m, 2H). ¹⁹FNMR (376 MHz, CDCl₃) δ −119.81 (dd, J=11.0, 7.9 Hz). LRMS, m/z: 388.07(M+Na)+, 364.03 (M-1).

iii. Example 2:1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethan-1-one

¹H NMR (500 MHz, Chloroform-d) δ 7.27 (d, J=14.5 Hz, 1H), 7.05-6.77 (m,4H), 3.89-3.51 (m, 10H), 2.18-1.97 (m, 1H), 1.06-0.87 (m, 2H), 0.72 (dd,J=5.1, 1.8 Hz, 2H). ESI-MS (M+1): 375.52.

iv. Example 3:(S)-6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)-3-methylpiperazin-1-yl)pyridazine-3-carbonitrile

¹H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J=9.5 Hz, 1H), 6.96-6.66 (m,4H), 4.95-4.46 (m, 1H), 4.44-3.91 (m, 3H), 3.64 (s, 2H), 3.47-2.90 (m,3H), 2.05-1.91 (m, 2H), 1.16-1.05 (m, 3H), 0.90 (dd, J=8.3, 2.0 Hz, 2H),0.63 (d, J=5.3 Hz, 2H). ESI-MS (M+1): 380.52.

v. Example 4:(R)-6-(4-(2-(4-cyclopropyl-3-fluorophenyl)acetyl)-3-methylpiperazin-1-yl)pyridazine-3-carbonitrile

¹H NMR (500 MHz, Chloroform-d) δ 7.40 (d, J=9.4 Hz, 1H), 6.95-6.65 (m,4H), 4.93-4.45 (m, 1H), 4.44-3.89 (m, 3H), 3.76-3.58 (m, 2H), 3.46-2.91(m, 3H), 2.08-1.91 (m, 1H), 1.12 (d, J=6.6 Hz, 3H), 0.97-0.82 (m, 2H),0.68-0.55 (m, 2H). ESI-MS (M+1): 380.52.

vi. Example 5:(R)-1-(4-(6-chloropyridazin-3-yl)-2-methylpiperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethan-1-one

¹H NMR (500 MHz, Chloroform-d) δ 7.26-7.12 (m, 1H), 6.93-6.71 (m, 4H),4.92-4.39 (m, 1H), 4.30-3.74 (m, 3H), 3.64 (s, 2H), 3.45-2.91 (m, 3H),1.97 (td, J=8.4, 4.3 Hz, 1H), 1.18-1.08 (m, 3H), 0.95-0.82 (m, 2H),0.69-0.53 (m, 2H). ESI-MS (M+1): 389.42.

vii. Example 6:(S)-1-(4-(6-chloropyridazin-3-yl)-2-methylpiperazin-1-yl)-2-(4-cyclopropyl-3-fluorophenyl)ethan-1-one

¹H NMR (500 MHz, Chloroform-d) δ 7.24-7.09 (m, 1H), 6.92-6.63 (m, 4H),4.95-4.40 (m, 1H), 4.31-3.74 (m, 3H), 3.64 (s, 2H), 3.44-3.15 (m, 1H),3.15-2.75 (m, 2H), 2.03-1.91 (m, 1H), 1.17-1.06 (m, 3H), 0.95-0.83 (m,2H), 0.63 (dd, J=5.2, 1.8 Hz, 2H). ESI-MS (M+1): 389.42.

viii. Example 7:1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)-2-(4-cyclopropylphenyl)ethan-1-one

¹H NMR (500 MHz, Chloroform-d) δ 7.31-7.11 (m, 1H), 7.07 (d, J=7.8 Hz,2H), 6.95 (d, J=7.8 Hz, 2H), 6.81 (d, J=9.5 Hz, 1H), 3.86-3.27 (m, 8H),1.88-1.74 (m, 1H), 0.96-0.77 (m, 2H), 0.59 (d, J=5.2 Hz, 2H). ESI-MS(M+1): 357.31.

ix. Example 8;(r)-6-(4-(2-(4-cyclopropylphenyl)acetyl)-3-methylpiperazin-1-yl)pyridazine-3-carbonitrile

¹H NMR (500 MHz, Chloroform-d) δ 7.38 (d, J=9.6 Hz, 1H), 7.05 (d, J=6.9Hz, 2H), 6.95 (d, J=7.8 Hz, 2H), 6.78-6.63 (m, 1H), 4.97-4.45 (m, 1H),4.38-3.91 (m, 2H), 3.79-3.59 (m, 3H), 3.45-2.98 (m, 3H), 1.79 (ddd,J=13.5, 8.7, 5.1 Hz, 1H), 1.10 (d, J=6.7 Hz, 3H), 0.94-0.81 (m, 2H),0.66-0.53 (m, 2H). ESI-MS (M+1): 362.56.

x. Example 9;(s)-6-(4-(2-(4-cyclopropylphenyl)acetyl)-3-methylpiperazin-1-yl)pyridazine-3-carbonitrile

¹H NMR (500 MHz, Chloroform-d) δ 7.47 (d, J=9.6 Hz, 1H), 7.14 (d, J=6.9Hz, 2H), 7.04 (d, J=7.7 Hz, 2H), 6.91-6.70 (m, 1H), 4.79 (dd, J=170.2,10.0 Hz, 1H), 4.48-3.98 (m, 2H), 3.86-3.69 (m, 3H), 3.55-2.93 (m, 3H),1.88 (tt, J=8.6, 5.0 Hz, 1H), 1.19 (d, J=6.7 Hz, 3H), 0.97 (dd, J=8.4,2.1 Hz, 2H), 0.73-0.63 (m, 2H). ESI-MS (M+1): 362.47.

xi. Example 10;(r)-1-(4-(6-chloropyridazin-3-yl)-2-methylpiperazin-1-yl)-2-(4-cyclopropylphenyl)ethan-1-one

¹H NMR (500 MHz, DMSO-d₆) δ 7.53 (d, J=9.6 Hz, 1H), 7.38 (dt, J=14.5,6.0 Hz, 1H), 7.11 (dd, J=12.5, 7.4 Hz, 2H), 7.01 (d, J=7.7 Hz, 2H),4.71-4.20 (m, 2H), 4.18-4.05 (m, 2H), 3.92-3.56 (m, 3H), 3.26-2.80 (m,2H), 1.88 (tt, J=8.5, 5.1 Hz, 1H), 1.05 (d, J=6.6 Hz, 3H), 0.92 (dd,J=8.5, 2.2 Hz, 2H), 0.70-0.56 (m, 2H). ESI-MS (M+1): 371.42.

2. Characterization of Exemplary Compounds

The compounds below in Table 1 were synthesized with methods identicalor analogous to those described herein. The requisite starting materialswere commercially available, described in the literature, or readilysynthesized by one skilled in the art of organic synthesis.

TABLE 1 No. Structure hPanK3 IC₅₀ (nM) 1

8.9 ± 0.8 2

2.9 ± 0.5 3

6.5 ± 0.8 4

12.5 ± 1.5  5

6.9 ± 0.6 6

2.2 ± 0.3 7

5.8 ± 0.4 8

12.9 ± 1.8  9

5.2 ± 0.6 10

3.8 ± 0.4

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

What is claimed is:
 1. A compound having a structure represented by aformula:

wherein Q² is a structure selected from:

wherein each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, provided at leastone of R^(3a), R^(3b), and R^(3c) is halogen; and wherein R⁴ is selectedform hydrogen, halogen, —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃, and NO₂, or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1,wherein Q² is a structure selected from:


3. The compound of claim 1, wherein Q² is a structure selected from:


4. The compound of claim 1, wherein Q² is a structure:


5. The compound of claim 1, wherein R^(3a) is halogen.
 6. The compoundof claim 1, wherein R^(3a) is —F.
 7. The compound of claim 1, whereinR^(3a) is halogen and each of R^(3b) and R^(3c) is hydrogen.
 8. Thecompound of claim 1, wherein R^(3a) is —F and each of R^(3b) and R^(3c)is hydrogen.
 9. The compound of claim 1, wherein R^(3c) is halogen. 10.The compound of claim 1, wherein R^(3c) is —F.
 11. The compound of claim1, wherein each of R^(3a) and R^(3c) is —F and R^(3b) is hydrogen. 12.The compound of claim 1, wherein R⁴ is —CN.
 13. The compound of claim 1,wherein R⁴ is —Cl.
 14. The compound of claim 1, wherein the compound hasa structure:


15. The compound of claim 1, wherein the compound is selected from:


16. The compound of claim 1, wherein the compound is selected from:


17. A compound having a structure represented by a formula:

wherein A is selected from O, CO, CH₂, CF₂, NH, N(CH₃), and CH(OH);wherein each of R^(3a), R^(3b), and R^(3c) is independently selectedfrom hydrogen, halogen, C1-C4 alkoxy and C1-C4 alkyl, provided at leastone of R^(3a), R^(3b), and R^(3c) is halogen; and wherein R⁴ is selectedform hydrogen, halogen, —CN, SO₂NH₂, SO₂CH₃, SO₂CF₃, and NO₂, or apharmaceutically acceptable salt thereof.
 18. The compound of claim 0,wherein R^(3a) is halogen.
 19. The compound of claim 0, wherein R^(3a)is —F.
 20. The compound of claim 0, wherein R^(3a) is halogen and eachof R^(3b) and R^(3c) is hydrogen.
 21. The compound of claim 0, whereinR^(3a) is —F and each of R^(3b) and R^(3c) is hydrogen.
 22. The compoundof claim 0, wherein R^(3c) is halogen.
 23. The compound of claim 0,wherein R^(3c) is —F.
 24. The compound of claim 0, wherein each ofR^(3a) and R^(c) is —F and R^(3b) is hydrogen.
 25. The compound of claim0, wherein R⁴ is —CN.
 26. The compound of claim 0, wherein R⁴ is —Cl.27. The compound of claim 0, wherein the compound is selected from:


28. A method of modulating pantothenate kinase activity in at least onecell, the method comprising the step of contacting at least one cellwith an effective amount of at least one compound of claim 1 or claim 0,or a pharmaceutically acceptable salt thereof.
 29. The method of claim28, wherein modulating is inhibiting.
 30. The method of claim 29,wherein the cell is involved in a pathology characterized byheteromorphism of the gene associated with the enzyme pantothenatekinase.
 31. The method of claim 29, wherein the cell is involved in apathology characterized by misregulation of expression of the geneassociated with the enzyme pantothenate kinase.
 32. The method of claim28, wherein modulating is activating.
 33. The method of claim 32,wherein the cell is involved in a pathology characterized byheteromorphism of the gene associated with the enzyme pantothenatekinase.
 34. The method of claim 32, wherein the cell is involved in apathology characterized by misregulation of expression of the geneassociated with the enzyme pantothenate kinase.
 35. A method of treatinga disorder associated with pantothenate kinase activity in a subject,the method comprising administering to the subject an effective amountof at least one compound of claim 1 or claim 0, or a pharmaceuticallyacceptable salt thereof.
 36. The method of claim 35, further comprisingadministering to the subject an effective amount pantothenate and/orpantothenic acid.
 37. The method of claim 35, wherein the disorderassociated with pantothenate kinase activity is associated withmisregulated and/or elevated coenzyme A resulting in hyperglycemia. 38.The method of claim 35, wherein the disorder associated withpantothenate kinase activity is associated with a deficiency ofpantothenate kinase or coenzyme A resulting in neurodegeneration. 39.The method of claim 35, wherein the subject suffers fromneurodegeneration with brain iron accumulation or neurological disordercharacterized by reduced mitochondrial function.
 40. The method of claim35, wherein the disorder associated with pantothenate kinase activity isselected from dystonia, extrapyramidal effects, dysphagia, musclerigidity and/or limb stiffness, choreoathetosis, tremor, dementia,spasticity, muscle weakness, or seizure.